1. Field the Invention
The present invention relates to methods for treating and preventing fibrosis and fibrosis-associated conditions.
2. Background Art
Injury to any organ typically leads to a physiological response involving platelet-induced hemostasis, followed by an influx of inflammatory cells and activated fibroblasts. Cytokines produced by these cell types drive the formation of new extracellular matrix and blood vessels, which collectively form granulation tissue. The formation of fibrous tissue is part of the normal beneficial process of healing following injury; fibrosis, however, is a condition characterized by an abnormal accumulation of a collagen matrix following injury or inflammation that alters the structure and function of various tissues. Progressive fibrosis in the kidney, liver, lung, heart, bone, bone marrow, and skin is a major cause of, or contributor to, death.
Many of the diseases associated with the proliferation of fibrous tissue are chronic and often debilitating and include, for example, skin diseases such as scleroderma. Some, including pulmonary fibrosis, may be fatal, due in part to the fact that the current treatments have significant side effects and are generally not effective in slowing or halting the progression of fibrosis. There is, accordingly, a continuing need for new anti-fibrotic agents.
The IL-21 receptor (IL-21R) is a newly discovered member of the class I cytokine receptor family (Parrish-Novak et al. (2000) Nature 408:57-63; Ozaki et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97:11439-44). The IL-21 receptor shows significant sequence and structural homology with the IL-4 receptor alpha (IL-4Rα) chain and is adjacent to the IL-4Rα in the human and mouse genomes, while its ligand, IL-21, shares significant homology with the cytokines IL-2, IL4, and IL-15 (Sivakumar et al. (2004) Immunology 112:177-82; Habib et al. (2003) J. Allergy Clin. Immunol. 112:1033-45). IL-21 and IL-21R are thus newly described members of the gamma chain (γc)-dependent cytokine network because of their homology with cytokines and receptors that require the γc for functional signaling (Vosshenrich and Di Santo (2001) Curr. Biol. 11:R175-77). Because all members of the yc network exhibit important and unique roles in host immunity, there has been growing interest in dissecting the novel functions of the IL-21R during antigen-triggered immune responses in vivo.
Initial studies examining the function of IL-21 showed that NK cell expansion is antagonized, whereas antigen-specific T cell immunity is promoted by IL-21, including anti-tumor immunity (Ma et al. (2003) J. Immunol. 171:608-15; Kishida et al. (2003) Mol. Ther. 8:552-58; Di Carlo et al. (2004) J. Immunol. 172:1540-47), findings that suggest that IL-21 serves as a bridge between innate and adaptive immune responses (Collins et al. (2003) Immunol. Res. 28:131-40). IL-21 also regulates B cell and CD8+ T cell function in vivo (Ozaki et al. (2002) Science 298:1630-34; Suto et al. (2002) Blood 100:4565-73; Mehta et al. (2003) J. Immunol. 170:4111-18; Pene et al. (2004) J. Immunol. 172:5154-57; Jin et al. (2004) J. Immunol. 173:657-65; Zeng et al. (2005) J. Exp. Med. 201:139-48). Additional studies suggest that IL-21 is a TH2 cytokine that can inhibit the differentiation of naïve TH cells into IFN-γ-secreting TH1 cells (Wurster et al. (2002) J. Exp. Med. 196:969-77). Indeed, exogenous treatment with IL-21 potently inhibited IFN-γ production without affecting other TH1/TH2-associated cytokines, suggesting that the repression of IFN-γ by IL-21 is highly specific. Thus, by virtue of its ability to suppress the development of TH1 cells, it was hypothesized that IL-21 might promote TH2 responses (Wurster et al., supra). Nevertheless, the involvement of the IL-21R signaling pathway in TH2 response development was not previously investigated in any TH2-dependent disorder.
In schistosomiasis, TH2 cytokines play an indispensable role in the pathogenesis of the disease (Wynn (2004) Nat. Rev. Immunol. 4:583-594; Pearce and MacDonald (2002) Nat. Rev. Immunol. 2:499-511). Indeed, IL4/IL-13-, IL-4Rα-, and Stat6-deficient mice all show significantly impaired granuloma formation and liver fibrosis following infection with S. mansoni (Chiaramonte et al. (1999) J. Clin. Invest. 104:777-85; Kaplan et al. (1998) J. Immunol. 160:1850-56; Jankovic et al. (1999) J. Immunol. 163:337-42; Fallon et al. (2000) J. Immunol. 164:2585-91). Given the recent classification of IL-21 as a TH2 cytokine (Wurster et al. (2002), supra; Mehta et al. (2005). Proc. Natl. Acad. Sci. U.S.A. 102:2016-21), the striking similarities between the IL-4 and IL-21 receptors (Sivakumar et al., supra; Habib et al., supra), and the critical role of the related IL-4Rα/Stat6-signaling pathway in this disease as well as in other TH2 cytokine-driven inflammatory disorders (Wynn (2003) Annu. Rev. Immunol. 21:425-56), an important question evolving from these studies was whether IL-21R signaling plays a significant role in the initiation and/or maintenance of TH2 immunity.